Airway remodeling accompanies common pulmonary disorders including asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia and cystic fibrosis. Epithelial regeneration after injury is a key component in airway remodeling. Accordingly, cellular processes underlying the pathogenesis of lung disease include abnormalities in epithelial proliferation, differentiation and survival. The objective of the present proposal is to elucidate the role of the retinoblastoma family (Rb, p107 and p130) in lung morphogenesis and airway remodeling. The central hypothesis is that Rb family proteins act as distinct and critical regulators of epithelial proliferation, differentiation and survival both during development and in response to injury. Preliminary data demonstrate that Rb family proteins play an essential role in lung formation. In addition, Rb itself has an unexpected cell type specific function in the developing airway. Specifically, Rb is required for regulating neuroendocrine cell fate;cells known to play a central role in epithelial regeneration after injury. In contrast, other epithelial cell lineages are capable of compensating for loss of Rb function. This proposal is designed to 1) test the hypothesis that Rb deficiency results in deregulated epithelial regeneration after injury and subsequent development of lung disease, 2) test the hypothesis that timing of Rb inactivation in progenitor cells during development versus quiescent cells in the mature airway plays a fundamental role in determining phenotypic outcomes, and 3) elucidate the molecular mechanisms underlying cellular compensation for loss of Rb function. The studies will be performed in vivo by inducing Rb gene ablation in a temporal and lung epithelial specific manner in genetically modified mice. Effects of Rb family ablation (separately or in combination) on lung morphogenesis, cell cycle regulation and cell differentiation will be assessed. It is expected that these studies will result in a better understanding of epithelial biology and thus provide a solid foundation for development of novel therapies for lung disease.